Endometrial cancer (EC) ranks first in incidence and second in mortality among gynecological malignancies. The most common type of endometrial cancer, endometrioid adenocarcinoma, develops from endometrial hyperplasia. Although several molecular alterations have been identified, the molecular pathogenesis of endometrial cancer remains poorly understood. Clinical advances on endometrial cancer require the development of animal models paralleling the human disease. PTEN was identified as a candidate tumor-suppressor gene on chromosome 10q23, a genomic region deleted in a large number of tumors. More than 50% of human endometrial cancers of the endometrioid subtype harbor mutations or deletions in the PTEN locus. We hypothesize that PTEN inactivation per se plays a critical role in the early phases of endometrial cancer pathogenesis and that it cooperates with other genetic alterations in tumor progression. We propose to test this hypothesis and further characterize the molecular pathways by which PTEN suppresses endometrial tumorigenesis through a direct in vivo genetic approach and the following strategy: Aim 1. To define, in knockout mice the role of PTEN in endometrial cancer initiation and progression. PTEN mice develop endometrial complex atypical hyperplasia (CAH), a lesion that is considered the precursor of EC. We will elucidate the molecular mechanisms underlying endometrial cancer pathogenesis in these mice and whether the complete loss of PTEN is a prerequisite for endometrial tumorigenesis. Aim 2. To dissect in the PTEN mouse the multistep process towards endometrial cancer pathogenesis. We will define the molecular mechanisms underlying cooperative oncogenesis in these mice. We will determine whether PTEN haploinsufficiency and/or PTEN loss cooperate in endometrial cancer pathogenesis with the transforming ability of oncogenes, or whether it increases tumor incidence in mice lacking tumor-growth suppressor genes involved in endometrial cancer pathogenesis. Aim 3. To generate a mouse model of endometrial cancer by conditional PTEN inactivation. We will completely inactivate PTEN in the endometrial epithelium by a Cre-loxP mediated approach. These mice will be intercrossed with other mutants to study in vivo the mechanisms of endometrial tumorigenesis in a tissue specific manner.